Overall Program Abstract. Dendritic spines with abnormal morphology occur in various forms of mental retardation and are also found in psychiatric conditions associated with disturbances to memory and cognition. These widely reported observations raise the possibility that defects in the processes that regulate the spine actin cytoskeleton are a common final substrate for a broad array of learning disabilities. The present proposal, which is a revised application for renewal of PPG #P01NS045260, addresses this hypothesis and potential therapeutic strategies suggested by it. Work under the previous PPG award showed that the stabilization of long-term potentiation (LTP), a form of synaptic plasticity closely related to the encoding of lasting memory, is moderately to severely impaired in rodent models of five distinctly different types of memory disorder: middle-aging, early-stage Huntington's Disease (HD), Fragile-X Syndrome (FXS), early-life stress, and menopause. Evidence obtained with newly introduced light microscopic techniques indicates that LTP-related reorganization of the spine cytoskeleton is defective in at least three of these cases. Infusions of Brain-Derived Neurotrophic Factor (BDNF) rescued LTP in four of the models and restored activity-driven changes to the cytoskeleton in two so far studied. Increasing brain concentrations of BDNF, using daily drug regimens developed as one of goals the previous PPG, produces similar effects. The proposed studies have the following objectives: i) test the specific prediction that activity-driven cytoskeletal reorganization is abnormal in the different rodent models of memory impairment (this entails adding a mouse model of Angelman's Syndrome to those used in previous work);ii) identify reasons (enzyme, signaling abnormalities) contributing to cytoskeletal defects in the different models;and iii) test if chronic up-regulation of BDNF increases BDNF signaling at synapses and restores actin signaling in spines. There will be four subprojects, directed by different PIs: each with its own rodent models and with different aspects of cytoskeletal signaling as a focus. A Core facility will make up the fifth subproject and will provide analytical, administrative, and animal services for the program. In all, the proposed studies are expected to test for the presence of a common neurobiological defect contributing to synaptic plasticity and memory disorders of different origin and to evaluate a clinically relevant strategy for normalizing spine plasticity and behavior.